Full Length ArticleAtherosclerosis, myocardial infarction and primary hemostasis: Impact of platelets, von Willebrand factor and soluble glycoprotein VI
Introduction
Myocardial infarction (MI) is mainly caused by atherosclerosis [1]. While risk factors for atherosclerosis are extensively investigated, it remains controversial which factors lead to acute obstruction in patients with relevant atherosclerosis. Platelet adhesion and aggregation are central processes [1]. Beside platelets, subendothelial structures, coagulation proteins and rheologic factors are involved [2].
High platelet count (PLT) facilitates aggregation and increases secretion of thrombotic metabolites. Some authors confirmed a relationship between higher PLT and increased risk of adverse cardiovascular events [[3], [4], [5], [6], [7], [8]], others did not [3,[9], [10], [11]]. The effect on thrombus composition was shown by Kovács et al. [12].
Platelets with higher mean platelet volume (MPV) may contain more granules and be more effective [[13], [14], [15], [16], [17]]. MPV has been described as risk factor for an ACS [14,[17], [18], [19]] and was correlated with the severity of coronary artery disease (CAD) or mortality in patients with ACS [5,9,16,[20], [21], [22]]. Others failed to confirm such associations [10,20,23].
In blood vessels, erythrocytes concentrate centrally, whereas platelets are pushed to the wall. If hematocrit decreases, platelets adhere less effectively. A correlation between anemia and mortality in patients with ACS was demonstrated [24], but pathophysiology is explained non-hemostaseological.
Fibrinogen (FIB-C) facilitates platelet adhesion and cross linking of thrombocytes [25,26]. Sponder et al. observed a predictive correlation between fibrinogen and severity of CAD, confirming other studies [27]. Further, an association of fibrinogen and MI in contrast to unstable angina pectoris was shown [28]. Xu et al. found a link between fibrinogen and adverse cardiac events in patients with CAD [29]. In contrast, the extensive analysis of Ndrepepa et al. failed to identify fibrinogen as a risk factor for all-cause mortality [30].
The adhesion between subendothelial collagen and GPIb/IX/V on platelet surface is mediated by von Willebrand factor (vWF) and activates thrombocytes [25,26,[31], [32], [33]]. Metaanalyses conclude that elevated vWF is associated with major cardiovascular risk factors [[34], [35], [36]]. Several studies dealt with the association between vWF and the risk of CAD, MI or death following CAD in healthy subjects. Results were heterogeneous [[34], [35], [36], [37]] and little is known about the influence of the functionality of vWF expressed as ristocetin cofactor activity (vWF:RCo). We used vWF-ratio defined as vWF-antigen/ristocetin cofactor activity to overcome influence of acute phase reaction.
Glycoprotein VI (GPVI) is a collagen receptor on platelet surface mediating adhesion and activation [38], shed soluble GPVI (sGPVI) is a biomarker for platelet activation [39,40]. Higher expression of GPVI may lead to an easier activation of thrombocytes [41]. Elevated GPVI in patients with chest pain came along with higher risk for ACS and worse outcome. Further, GPVI was raised in patients with ambiguous ECG who finally suffered from ACS [42] and in patients with ACS in contrast to stable CAD. Patients with CAD presented with generally elevated levels of sGPVI [42]. Upregulated pathways for GPVI mediated platelet activation were found in patients with STEMI compared to CAD patients [41].
Recent works investigated antibodies against the GPVI-collagen-system as a target for antithrombotic therapy [43,44]. Diminishing the GPVI-function reduced platelet degranulation and platelet-endothelium interaction [45,46]. In a mouse model, the GPVI-antibody Revacept results in reduced infarct size [46] and in combination with low-dose thrombolysis in stroke, the therapy was effective but did not increase bleeding risk [47]. Further, it is under investigation in patients with stable CAD and symptomatic carotis stenosis, which highlights the importance of GPVI mediated adhesion of platelets in atherosclerosis [44].
In summary, the role of primary hemostasis in the development MI is still not known in detail. We aimed to identify risky constellations of primary hemostasis for MI in patients with CAD.
Section snippets
Materials and methods
Blood samples derive from 1491 patients from the Leipzig (LIFE) Heart Study [48]. All patients were suffering from coronary atherosclerosis with a lumen reduction of ≥50%. Group 0 includes only patients without MI and consists of patients either undergoing coronarangiography for the first time due to clinical suspiscion of coronary artery disease or patients with already known coronary artery disease. In the following, these are called non-MI CAD patients. Group 1 patients presented in the
Results
Men and women were analyzed separately mainly because of the different reference range of hematocrit in men and women. Analyzing men and women together, a distinction between non-MI CAD and MI by means of hematocrit is not possible because the distribution of high hematocrit values for women overlap with the normal range for men.
Metric data was described by measures of central tendency. Differences in distribution were calculated. Table 1 presents data of target parameters:
Hematocrit and sGPVI
Discussion
The risk to develop MI if atherosclerosis is manifest is still not predictable. The culprit lesion is often located proximal to the maximal stenosis [1]. Other factors besides degree of stenosis must influence time and severity of occlusion. We show the results of a large, well defined group of patients with manifest atherosclerosis with and without MI presenting data for primary hemostasis.
Conclusion
Many parameters may contribute to a vascular occlusion based on present atherosclerosis, but none of the biomarkers measured here is yet identified to have sole responsibility. The combination in a diagnostic model is regarded to identify patients at high risk, but our LVQ-model did not reveal a clinical useful score. A prospective, longitudinal model in which patients with CAD are monitored and investigated until the endpoint MI would be favorable. However, especially our results concerning
Sources of funding
The work was funded by Saxon State Ministry for Higher Education, Research and the Arts and supported by LIFE – Leipzig Research Center for Civilization Diseases, University Leipzig (LIFE-206 D32). LIFE is funded by the European Union, by the European Regional Development Fund (ERDF) and by the Free State of Saxony within the framework of the excellence initiative.
Contributors
JMV and TD collected the data, performed the analysis and wrote the manuscript, TV performed the calculation for LVQ and SOM. AT, RB and JT helped draft the manuscript and participated in study design and coordination. All authors read and approved the final manuscript.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
No prior presentation.
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